Circulating Memory B Cells in Early Multiple Sclerosis Exhibit Increased IgA+ Cells, Globally Decreased BAFF-R Expression and an EBV-Related IgM+ Cell Signature

Leffler, Jonatan; Trend, Stephanie; Ward, Natalie C.; Grau, Georges E.; Hawke, Simon; Byrne, Scott N.; Kermode, Allan G.; French, Martyn A.; Hart, Prue H.

doi:10.3389/fimmu.2022.812317

Cited by 11 publications

(17 citation statements)

References 59 publications

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“…Therefore, the higher number of IgA + CD20 + B cells in patients with MS prior to treatment with alemtuzumab compared with non‐MS controls may reflect an immunological rheostat attempting to contain the autoinflammation underway. Similar results were observed in a recent study 22 . This hypothesis is supported by the fact that these B‐cell subsets increase upon relapse .…”

Section: Discussionsupporting

confidence: 90%

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Peripheral B‐cell dysregulation is associated with relapse after long‐term quiescence in patients with multiple sclerosis

et al. 2022

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B cells play a major role in multiple sclerosis (MS), with many successful therapeutics capable of removing them from circulation. One such therapy, alemtuzumab, is thought to reset the immune system without the need for ongoing therapy in a proportion of patients. The exact cells contributing to disease pathogenesis and quiescence remain to be identified. We utilized mass cytometry to analyze B cells from the blood of patients with relapse-remitting MS (RRMS) before and after alemtuzumab treatment, and during relapse. A complementary RRMS cohort was analyzed by single-cell RNA sequencing. The R package "Spectre" was used to analyze these data, incorporating FlowSOM clustering, sparse partial least squares-discriminant analysis and permutational multivariate analysis of variance. Immunoglobulin (Ig)A + and IgG 1 + B-cell numbers were altered, including higher IgG 1 + B cells during relapse. B-cell linker protein (BLNK), CD40 and CD210 expression by B cells was lower in patients with RRMS compared with non-MS controls, with similar results at the transcriptomic level. Finally, alemtuzumab restored BLNK, CD40 and CD210 expression by IgA + and IgG 1 + B cells, which was altered again during relapse. These data suggest that impairment of IgA + and IgG 1 + B cells may contribute to MS pathogenesis, which can be restored by alemtuzumab.

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Section: Discussionsupporting

confidence: 90%

“…Similar results were observed in a recent study. 22 This hypothesis is supported by the fact that these B-cell subsets increase upon relapse.…”

Section: Discussionmentioning

confidence: 95%

Peripheral B‐cell dysregulation is associated with relapse after long‐term quiescence in patients with multiple sclerosis

et al. 2022

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“…In addition to studying atMBC responses to stimuli in the context of established EBV latency, we asked whether de novo infection itself was sufficient to induce an atMBC-like phenotype. Specifically, recent work has reported an association between EBV infection and a neuroinvasive, pathogenic subset of T-bet + /CXCR3 + B cells identified within clinically isolated syndrome (CIS)/multiple sclerosis (MS) patients ( 151 – 153 ). To address this possibility, we performed time-resolved FACS experiments to determine whether CXCR3-expressing B cells were induced during the early stages of EBV infection.…”

Section: Resultsmentioning

confidence: 99%

Epstein-Barr virus perpetuates B cell germinal center dynamics and generation of autoimmune-associated phenotypes in vitro

et al. 2022

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Human B cells encompass functionally diverse lineages and phenotypic states that contribute to protective as well as pathogenic responses. Epstein-Barr virus (EBV) provides a unique lens for studying heterogeneous B cell responses, given its adaptation to manipulate intrinsic cell programming. EBV promotes the activation, proliferation, and eventual outgrowth of host B cells as immortalized lymphoblastoid cell lines (LCLs) in vitro, which provide a foundational model of viral latency and lymphomagenesis. Although cellular responses and outcomes of infection can vary significantly within populations, investigations that capture genome-wide perspectives of this variation at single-cell resolution are in nascent stages. We have recently used single-cell approaches to identify EBV-mediated B cell heterogeneity in de novo infection and within LCLs, underscoring the dynamic and complex qualities of latent infection rather than a singular, static infection state. Here, we expand upon these findings with functional characterizations of EBV-induced dynamic phenotypes that mimic B cell immune responses. We found that distinct subpopulations isolated from LCLs could completely reconstitute the full phenotypic spectrum of their parental lines. In conjunction with conserved patterns of cell state diversity identified within scRNA-seq data, these data support a model in which EBV continuously drives recurrent B cell entry, progression through, and egress from the Germinal Center (GC) reaction. This “perpetual GC” also generates tangent cell fate trajectories including terminal plasmablast differentiation, which constitutes a replicative cul-de-sac for EBV from which lytic reactivation provides escape. Furthermore, we found that both established EBV latency and de novo infection support the development of cells with features of atypical memory B cells, which have been broadly associated with autoimmune disorders. Treatment of LCLs with TLR7 agonist or IL-21 was sufficient to generate an increased frequency of IgD-/CD27-/CD23-/CD38+/CD138+ plasmablasts. Separately, de novo EBV infection led to the development of CXCR3+/CD11c+/FCRL4+ B cells within days, providing evidence for possible T cell-independent origins of a recently described EBV-associated neuroinvasive CXCR3+ B cell subset in patients with multiple sclerosis. Collectively, this work reveals unexpected virus-driven complexity across infected cell populations and highlights potential roles of EBV in mediating or priming foundational aspects of virus-associated immune cell dysfunction in disease.

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“…An antigen presentation role for B cells, independent of autoantibody production, has been established in multiple sclerosis (MS) ( 90 ). Indeed, surface MHC-II expression was increased in B cells from relapsing MS patients ( 91 ), and this increase may be mechanistically linked to Epstein-Barr virus (EBV) infection ( 92 ). In animal models, B cell antigen presentation was sufficient to drive neuro-inflammation ( 93 ).…”

Section: Introductionmentioning

confidence: 99%

The Ins and Outs of Antigen Uptake in B cells

McShane

Malinova

2022

Front. Immunol.

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A review of our current knowledge of B cell antigen uptake mechanisms, the relevance of these processes to pathology, and outstanding questions in the field. Specific antigens induce B cell activation through the B cell receptor (BCR) which initiates downstream signaling and undergoes endocytosis. While extensive research has shed light on the signaling pathways in health and disease, the endocytic mechanisms remain largely uncharacterized. Given the importance of BCR-antigen internalization for antigen presentation in initiating adaptive immune responses and its role in autoimmunity and malignancy, understanding the molecular mechanisms represents critical, and largely untapped, potential therapeutics. In this review, we discuss recent advancements in our understanding of BCR endocytic mechanisms and the role of the actin cytoskeleton and post-translational modifications in regulating BCR uptake. We discuss dysregulated BCR endocytosis in the context of B cell malignancies and autoimmune disorders. Finally, we pose several outstanding mechanistic questions which will critically advance our understanding of the coordination between BCR endocytosis and B cell activation.

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Circulating Memory B Cells in Early Multiple Sclerosis Exhibit Increased IgA+ Cells, Globally Decreased BAFF-R Expression and an EBV-Related IgM+ Cell Signature

Cited by 11 publications

References 59 publications

Peripheral B‐cell dysregulation is associated with relapse after long‐term quiescence in patients with multiple sclerosis

Peripheral B‐cell dysregulation is associated with relapse after long‐term quiescence in patients with multiple sclerosis

Epstein-Barr virus perpetuates B cell germinal center dynamics and generation of autoimmune-associated phenotypes in vitro

The Ins and Outs of Antigen Uptake in B cells

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